Clefts of the lip and/or palate are common birth defects with a substantial economic and societal burden. They require extensive surgical, dental, speech, pediatric, hearing and behavioral interventions. While there are over 400 individual rare causes of clefting, approximately 70% are considered isolated or non-syndromic and the result of multiple gene-gene and gene environment interactions. After more than a decade of etiologic investigations in which there were only relatively modest advances, in the last few years new opportunities and technologies are benefiting the field. Gene identification has improved from an emphasis on careful family collection and phenotyping, advances in high throughput genotyping, powerful new analytic strategies, fine-structure mapping and mutation characterization, and the application of genomic tools to gene finding. This project will integrate closely with other projects and cores of this P50 center and to build on our previous experience with these approaches and with many of its collaborators. We will exploit the currently available high quality human genomic sequence to undertake an innovative approach to gene finding using genomic rearrangements to identify genes involved in CL/P. We will build on a productive collaboration of the Lidral, Marazita and Murray Labs in which we have already identified a novel CLIP locus with a LOD of 6.6 on 9q to fine map and identify this gene. Finally, in a parallel but conceptually different approach we will make use of individuals born of ancestrally mixed populations (African, European, American Indian) to identify genomic segments likely to contain genes of major effect in CLIP. We will pursue fine-mapping of these loci assisted by global gene expression analysis developed through the collaborators in Core E. Our project will be closely integrated with that of Marazita to use sub-phenotyping, including three-dimensional facial imaging to provide a better understanding of facial development. This project will in turn feed those of the mouse model projects as well as the fuctional analysis and expression cores to provide resources for their development of a better understanding of the basic biology of the genes that underlie clefts. By identifying genes playing a role in the etiology of cleft lip and palate we can advance basic biology and improve clinical care.